Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Trial Contact Information
Registry Information

Alternate Title

Melphalan and Buthionine Sulfoximine Followed by Bone Marrow or Peripheral Stem Cell Transplantation in Treating Children With Resistant or Recurrent Neuroblastoma

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Treatment	Active	Over 9 months to 30 years	Other	NANT-99-02 68, N99-02, CHLA-LA-NANT-99-02, CHLA-CCI-00.020, NCT00005835

Objectives

1. Determine the maximum tolerated dose of melphalan when combined with buthionine sulfoximine and followed by autologous bone marrow or peripheral blood stem cell support in children with resistant or recurrent high-risk neuroblastoma.
2. Assess the toxic effects of this regimen in these patients.
3. Determine the pharmacokinetics of this regimen in these patients.
4. Determine the response rate of patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• Diagnosis of high-risk neuroblastoma confirmed by histology and/or tumor cells in bone marrow with elevated urinary catecholamine metabolites
• Meets 1 of the following response status criteria:
  • Current or previous progressive disease
  • Mixed or no response following completion of minimum of 4 courses of induction therapy
• Meets 1 of the following criteria:
  • Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan
  • Metaiodobenzylguanidine (MIBG) scan with uptake at a minimum of one site
  • Bone marrow disease documented by standard morphology of bilateral bone marrow aspirate and biopsy specimens
    • Documentation by positive immunocytology is not sufficient
  • Biopsy of a lesion seen on bone scan that is non-avid for MIBG and that demonstrates viable neuroblastoma
• Meets 1 of the following criteria for harvested autologous stem cells:
  • Availability of at least 1.5 x 10⁶ CD34-positive unpurged autologous peripheral blood stem cells per kg of body weight*
  • Availability of at least 1.0 x 10⁶ viable CD34-positive purged autologous peripheral blood stem cells per kg of body weight*
    • A backup source of stem cells is required if there are < 1.5 x 10⁶ CD34-positive viable cells/kg available for infusion
  • Availability of at least 1 x 10⁸ purged autologous mononuclear bone marrow cells per kg of body weight*

   [Note: *Product to be infused must have 0 tumor cells by immunocytology]

• No history of intraparenchymal brain lesion
• No concurrent intraparenchymal brain lesion or meningeal/parameningeal soft tissue mass extending directly into the cranial cavity by CT, MRI, or metaiodobenzylguanidine scan

Prior/Concurrent Therapy:

Biologic therapy:

• See Disease Characteristics
• At least 3 weeks since prior biologic therapy and recovered

Chemotherapy:

• At least 3 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered
• No other concurrent anticancer chemotherapy

Endocrine therapy:

• Not specified

Radiotherapy:

• Recovered from prior radiotherapy
• Prior diagnostic radiotherapy allowed
• More than 6 months since prior radiotherapy to mantle and Y ports
• More than 3 months since prior therapeutic metaiodobenzylguanidine (¹³¹I-MIBG) and no more than 20 mCl/kg total dose received
• At least 2 weeks since prior radiotherapy to all other sites
• More than 6 months since prior radiotherapy to kidneys, liver, heart, skull, or face
  • No more than 25% of the liver can have received > 1800 cGy
  • No more than 20% of one of the kidneys can have received > 1200 cGy
  • No more than a 10 cc volume of the brain can have received > 1000 cGy
• No prior total body irradiation
• No prior total cranial or craniospinal radiotherapy
• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• Recovered from any prior therapy
• At least 7 days since prior antibiotics, antifungals, or antivirals
• No acetaminophen or cephalosporin antibiotics for at least 7 days before, during, and until at least 2 weeks after buthionine sulfoximine infusion
• No prophylactic antimicrobials (i.e., nystatin or sulfamethoxazole/trimethoprim) for at least 7 days before, during, and until at least 7 days after buthionine sulfoximine infusion
• No concurrent antiretroviral medications for HIV-positive patients

Patient Characteristics:

Age:

• Over 9 months to 30 years

Performance status:

• ECOG or Zubrod 0-1

Life expectancy:

• At least 2 months

Hematopoietic:

• Absolute neutrophil count at least 500/mm³
• Platelet count at least 20,000/mm³ (transfusion allowed)
• Hemoglobin at least 10 g/dL (transfusion allowed)

Hepatic:

• Bilirubin normal
• AST and ALT no greater than 2.5 times normal
• No active hepatitis if HIV positive

Renal:

• Glomerular filtration rate or creatinine clearance ≥ 100 mL/min
• Creatinine ≤ 1.5 times normal

Cardiovascular:

• Ejection fraction at least 55% by echocardiogram or MUGA scan

  OR

• Fractional shortening at least 30% by echocardiogram

Pulmonary:

• No dyspnea at rest or exercise intolerance
• No active pneumonia if HIV positive

Neurologic:

• No grade 1 or greater neurological function abnormality except grade 1 irritability, headache, dizziness, insomnia, or somnolence (if due to narcotic analgesics)
• No history of seizures

Other:

• No other active health problems if HIV positive
• No concurrent neoplastic or nonneoplastic disease of any major organ system that would preclude study participation
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

A total of 30 patients will be accrued for this study within 2-3 years.

Outline

This is a multicenter, dose-escalation study of melphalan.

Patients receive buthionine sulfoximine IV as a bolus over 30 minutes followed by a 72-hour continuous infusion beginning on day -4; melphalan IV over 15 minutes on days -3 and -2; autologous peripheral blood stem cells or bone marrow IV over 15-30 minutes on day 0; and filgrastim (G-CSF) subcutaneously or IV once daily beginning on day 0 and continuing until blood counts recover.

Cohorts of 3-6 patients receive escalating doses of melphalan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

Patients are followed at 84 days and then 2 months later if there is a complete and/or partial response. Patients who continue therapy on other protocols are followed before starting the new therapy. All patients are followed for life for any delayed toxic effects to protocol therapy and secondary malignancies.

Trial Contact Information

Trial Lead Organizations

New Approaches to Neuroblastoma Therapy Consortium

Judith Villablanca, MD, Protocol chair		Ph: 323-361-5654 Email: jvillablanca@chla.usc.edu

U.S.A.
California
	Los Angeles
	Childrens Hospital Los Angeles
		Judith Villablanca, MD	Ph:  323-361-5654
			Email: jvillablanca@chla.usc.edu
	Palo Alto
	Lucile Packard Children's Hospital at Stanford University Medical Center
		Clare Twist, MD	Ph:  650-723-5535
	San Francisco
	UCSF Helen Diller Family Comprehensive Cancer Center
		Katherine Matthay, MD	Ph:  415-476-3831
Illinois
	Chicago
	University of Chicago Comer Children's Hospital
		Susan Cohn, MD	Ph:  773-703-2571 800-289-6333
			Email: scohn@peds.bsd.uchicago.edu
Michigan
	Ann Arbor
	University of Michigan Comprehensive Cancer Center
		Gregory Yanik, MD	Ph:  734-936-8785
			Email: gyanik@umich.edu
Ohio
	Cincinnati
	Cincinnati Children's Hospital Medical Center
		John Perentesis, MD	Ph:  513-636-6090
			Email: john.perentesis@chmcc.org
Pennsylvania
	Philadelphia
	Children's Hospital of Philadelphia
		John Maris, MD	Ph:  215-590-5242
			Email: maris@chop.edu
Texas
	Fort Worth
	Cook Children's Medical Center - Fort Worth
		Clinical Trials Office - Cook's Children's Medical Center	Ph:  682-885-2103
Washington
	Seattle
	Children's Hospital and Regional Medical Center - Seattle
		Julie Park, MD	Ph:  206-987-2106
Canada
Ontario
	Toronto
	Hospital for Sick Children
		Sylvain Baruchel, MD	Ph:  416-813-7795

Registry Information
Official Title		Modulation of Intensive Melphalan (L-PAM) by Buthionine Sulfoximine (BSO) Autologous Stem Cell Support for Resistant or Recurrent High-Risk Neuroblastoma (IND 69-112)
Trial Start Date		2001-08-08
Trial Completion Date		2009-12-31 (estimated)
Registered in ClinicalTrials.gov		NCT00005835
Date Submitted to PDQ		2000-03-28
Information Last Verified		2009-06-14
NCI Grant/Contract Number		CA81403

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